A Pseudohypervalent Sulfur Intermediate as an Oxidative Protective Mechanism in the Archaea Peroxiredoxin Enzyme ApTPx

Abstract

Peroxiredoxins (Prxs) are a ubiquitous class of enzymes that have central roles in a number of important physiological processes. Using a multiscale computational approach, we have investigated the mechanism by which the active-site cysteine (Cys50) in the typical 2-Cys Prx from Archaea (ApTPx) is oxidized by HO to sulfenic acid. In addition, its further oxidation to give a sulfinic acid and its possible alternate intramolecular reaction to form an experimentally proposed hypervalent sulfurane were examined. Oxidation of Cys50 by HO to give the sulfenic acid intermediate occurs in one step with a barrier of 82.1 kJ mol. A two-step pathway is proposed with a very low barrier of 16.5 kJ mol by which it can subsequently react with an adjacent histidyl (His42) to form the pseudohypervalent sulfurane. This pathway also involves an adjacent aspartyl (Asp45), which helps alternate the protonation state of His42. The sulfurane's S···Nδ interaction was characterized using QTAIM, NCI, and NBO analyses and found to be a noncovalent interaction. Notably, this bond helps orient the SOH moiety such that it is less susceptible to oxidation by HO to sulfinic acid. Significantly, sulfurane formation is energetically favored to further HO oxidation of SOH to a sulfinic acid, providing a mechanism by which the active-site Cys50 is protected against overoxidation.

Unraveling the Critical Role Played by Ado762′OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase

“…Using MOE and the NAMD program, we submitted the resulting minimized model for unconstrained 10 ns MD simulation with a time step of 2 fs under constant pressure and temperature until the system reached equilibrium using a protocol we have successfully used in related studies. − It is noted that the default settings of MOE were used, which includes use of the PME method for calculating Coulombic interactions, cutoffs for nonbonded long-range interactions of between 8 and 10 Å, and tether ranges from 0 to 100 Å applied to all heavy atoms. Furthermore, the standard protocol that is encoded in MOE was used to parametrize any ligands using the Amber12 force field.…”

Disulfidptosis: A new type of cell death

“…The process is also tightly controlled by molecules like GAPDH, Trx, and Prx [108][109][110], and pathways such as NF-κB [111,112] and JNK [113], which regulate redox levels, protein synthesis, and function. These interactions reveal a complex regulatory network underlying disulfidptosis, with profound impacts on cellular health and disease susceptibility.…”

Redox and Thiols in Archaea

“…InterPro (IPR000889) search of GSH peroxidases yielded 102 archaeal hits (Figure 2) suggesting that either a GSH or γGC dependent peroxidase may exist in archaea. Peroxiredoxins (Prxs), thiol-dependent peroxidases that scavenge peroxides, have been identified in archaea [68][69][70][71][72][73][74][75]. In particular, the S. solfataricus Prx is shown to use a thiol relay system in which the GRX-like PDO accepts reductant from NTR to reactivate the Prx in its catalytic cycle [68][69][70][71][72][73][74][75][76].…”